EpiPen Familiarity May Prove Tough Hurdle For Generics

With EpiPen injector patent-protected and patients accustomed to its use, finding a substitutable generic device may prove difficult.

Sponsors and FDA may have a tough time developing and approving a non-Mylan NV sanctioned generic EpiPen (epinephrine), in part because any new product might have to overcome patients' familiarity with the brand competitor.

A different device already has been shown to potentially cause confusion, which is a concern because a generic could be automatically substituted for an EpiPen at the pharmacy.

And it appears to be a problem beyond just the complex generic arena. Some of FDA's first approved biosimilars are also dealing with presentation issues that could affect uptake.

The uniqueness of Epipen's injector system is the core of Mylan's patent defense; the injector's ubiquity is central to the firm's regulatory defense.

After a week of condemnation over its substantial price increases, Mylan announced that it would make an authorized generic of its EpiPen, which would cost about half as much as the brand version. (Also see "Mylan's Generic EpiPen: A Good PR Move, But Risks Alienating Payers" - Scrip, 29 Aug, 2016.)

Politicians and other stakeholders have hoped that other sponsors would enter the market and push the price down. But several so far have been unsuccessful, which has sparked questions about FDA's generic drug review process. (Also see "EpiPen Outrage In Congress Puts Spotlight On FDA Generic Review" - Pink Sheet, 29 Aug, 2016.)

The issue likely is related to the EpiPen injection device. Four patents are listed in the Orange Book, all related to the device, which do not expire until 2025.

It may be difficult to produce a device substantially different from EpiPen that is not also confusing to patients already familiar with how to use the EpiPen device.

The issue may have affected one potential competitor already.

Citizen Petition Study Raised Injector Issues

Teva Pharmaceutical Industries Ltd. had filed an EpiPen ANDA, and Mylan was fighting to keep it off the market. The company filed a citizen petition in January 2015 arguing that Teva's product should not be approved until comparative performance tests are completed and FDA determines that patients can operate the Teva device using EpiPen instructions. (Also see "Mylan’s EpiPen Defense Against Generics Focuses On Device Design" - Pink Sheet, 22 Jan, 2015.)

As part of its petition, Mylan submitted a study in May 2015 suggesting that what was thought to be a potential Teva epinephrine device may not work with EpiPen operating instructions.

Interface Analysis Associates of Saratoga, Calif., conducted the study, which compared EpiPen to a prototype of an epinephrine injector "understood to be very similar to the Vibex platform auto-injector" used with the drug Otrexup (methotrexate). Antares Pharma Inc.designed the injector platform and is partnered with Teva for development in the US.

"Because the proposed generic device has design features similar to those of the EpiPen auto-injector … the participants assumed the device operation to be the same" –

Interface Analysis study

The study looked at whether those familiar with EpiPen could operate the alternative device in a simulated situation. The firm tested 15 people described as EpiPen patient caregivers with knowledge of the product and 15 people (nine adults and six children) who were EpiPen patients, according to the study report.

None were trained on how the proposed generic device should be used, based on the assumption that it would be substituted at the pharmacy and no training would be given.

Results indicated that both groups likely would try to use the Teva device like an EpiPen, which would result in a failed injection attempt. Nearly all of them, 28/30 participants, described the injection procedure incorrectly based on their viewing of the device. Two juvenile participants described the procedure correctly.

Of the 28 that failed, 27 "mimicked the exact EpiPen auto-injector procedure," according to the study report.

"Because the proposed generic device has design features similar to those of the EpiPen auto-injector … the participants assumed the device operation to be the same," Interface Analysis Founding Principal Anthony Andre said in the report.

"The proposed generic device has design features that trigger the learned behaviors associated with the EpiPen auto-injector and there is no strong design cue to suggest otherwise. The result is an injection attempt that mimics that of the EpiPen auto-injector, but because of important differences in operating principles, results in a failure to deliver therapy."

The potential generic device requires users to twist off the needle cap and then flip a safety clip before administering the injection by pushing the device against the thigh.

EpiPen is slightly different – users must pull a safety release off the injector without bending or twisting and then administer the injection by pushing the device against the outer thigh. No needle cap must be removed.

Only three study participants determined that the Teva device requires the user to remove the needle cap before giving the injection, unlike EpiPen. The cap has a hole that appears to allow the needle to pass through it, suggesting that like EpiPen, it did not need to be removed, according to the report.

Andre concluded that the results suggest it could be difficult for a competitor to create a device that could be automatically substitutable for an EpiPen.

"Because the proposed generic device likely will be substituted at the pharmacy without training and because users are unlikely to review the labeling or label (especially in an emergency) … it is unlikely that labeling would overcome the design cues that trigger the learned EpiPen auto-injector behaviors," Andre wrote in the report.

FDA denied the Mylan citizen petition in June 2015, in part because it determined that it was not appropriate to take action on a part of the application before taking final action on the ANDA.

In late February 2016, Teva announced that it had received a complete response letter that included "major deficiencies."

The company did not specify what issues were identified, but indicated that it did not expect to launch the product until 2017. (Also see "Mylan’s EpiPen Exclusivity Saved Again As Teva Reports CRL" - Pink Sheet, 1 Mar, 2016.)

During an investor briefing Sept. 9, Teva Global Generic Medicines CEO Sigurdur Olafsson said FDA has been more responsive to Teva's request for a meeting following the media attention.

But despite the increased spotlight on the need for a cheaper alternative, Olafsson said he still believes the earliest the company could get to market with a generic version of EpiPen is late 2017 or early 2018.

Problem Can Be Overcome And FDA Will Help

Aspiring generics of GlaxoSmithKline PLC's chronic obstructive pulmonary disease treatment Advair Diskus (fluticasone/salmeterol) also ran into device problems.

Even though the drug was off-patent, the inhaler remained protected, increasing the difficulty for competitors to enter. (Also see "How to overcome the 'double-lock' barrier to entry for generic inhalers" - Scrip, 17 Jun, 2015.)

Still a number of companies, including Teva and Mylan, are developing generic versions of the product now that the patent on the Diskus device will expire this year. (Also see "Mylan Sees A Difference In Having Generic Drug User Fees" - Pink Sheet, 10 Aug, 2016.)

More formal help for generic sponsors targeting complex products is on the way. As part of the generic drug user fee program renewal, FDA will allow meetings on complex generics, potentially to give sponsors advice on the best path forward for those applications. (Also see "GDUFA II Will Include Small Business Relief, Priority ANDA Reviews" - Pink Sheet, 31 Aug, 2016.)

Biosimilars Have Similar Problems

FDA likely will have to deal with similar issues once it begins considering interchangeability applications for biosimilars.

Sandoz Inc.'s Zarxio (filgrastim-sndz), which references Amgen Inc.'s Neupogen (filgrastim), faces concerns with differences with its prefilled syringe.

During the application review, FDA said patients and caregivers may have trouble administering partial doses. It eventually led to a statement added to the Zarxio label advising against going below a minimum dose. (Also see "Zarxio Syringe’s Limitations May Delay Decision On Neupogen Interchangeability" - Pink Sheet, 15 Jun, 2015.)

Sandoz's newly approved biosimilar of Amgen's Enbrel (etanercept), also has presentation concerns that could affect uptake, at least initially. (Also see "FDA Biosimilar Policy Continues To Evolve With Approval Of Sandoz Erelzi" - Pink Sheet, 30 Aug, 2016.)

Erelzi (etanercept-szzs) is available in prefilled syringes, but not a lyophilized powder like Enbrel, which likely will affect its pediatric use.

FDA included a statement in the Erelzi label that there is no weight-based dosing for children less than 63 kg, which is available with Enbrel.

The Pediatric Research Equity Act requires that Sandoz develop a pediatric dose, but Sandoz does not intend to introduce one until it applies for Erelzi to be ruled interchangeable with Enbrel.

In the meantime, physicians may not be able to use Erelzi in some children, which could further cement preference for the brand product no matter the price of the biosimilar. (Also see "Biosimilars' Pediatric Pressures Could Push Them Toward Interchangeability" - Pink Sheet, 15 Jul, 2016.)